Travis Thomson, PhD
Vivian Budnik, PhD
Scientists at UMass Medical School and the University of Utah have discovered a new form of cellular communication in the nervous system, according to two new papers published in the January issue of the journal Cell. Vivian Budnik, PhD, and Travis Thomson, PhD, served as co-corresponding authors of the UMMS paper; Jason Shepherd, PhD, led the paper completed by the University of Utah.
By studying neuromuscular junctions of fruit flies and cultured neurons from mammals, Drs. Budnik, Thomson and Shepherd show that this new communication mechanism resembles aspects of the behavior of retroviruses, such as HIV, during the propagation of an infection.
“Linchpins of neurological disorders such as schizophrenia and addiction are abnormalities in mechanisms of signal transfer across cells in the nervous system,” said Budnik, the Worcester Foundation for Biomedical Research Chair and chair and professor of neurobiology. “Thus, unraveling these mechanisms will likely provide important clues to understand and treat these devastating diseases.”
Previous work in the Budnik lab documented the use of extracellular vesicles (EVs), which are membrane-bound packets containing cellular materials, to send maturation signals across synaptic contacts, such as those found in the neuromuscular junction. To elucidate the composition of EVs, the authors set out to find out which RNAs were loaded into EVs. They found that an RNA named Arc—a master regulator of synaptic plasticity, as well as of learning and memory in mammals—was particularly enriched in EVs.
The Arc protein shares many similarities with proteins that assemble into the capsid that encases the retroviral RNA genome. Budnik and colleagues found that the Arc protein assembles into a capsid-like particle that encases Arc RNA. The Arc capsid and its mRNA content are then released in EVs and taken up by a synaptic partner, such as the muscles at the neuromuscular junction or the dendritic spines in mammalian neurons.
“Interestingly, Arc RNA has a specific signature at its unstranslated region that directs its loading into extracellular vesicles,” said Thomson, assistant professor of neurobiology. “Blocking the transfer of Arc EVs through mutations in the Arc gene or elimination of the specific signature results in neuromuscular junctions that fail to mature or show changes in response to an intense stimulus. This suggests that this communication mechanism has an important function in shaping synaptic connections.”
Another intriguing aspect of the UMMS study is the finding that a fruit fly retrotransposon behaves in a manner similar to Arc. (Retrotransposons are permanent residents of the genome, thought to be derived from retroviruses. Entire retrotransposons or retrotransposon fragments occupy approximately 50 percent of the human genome and have been postulated to represent “junk DNA” because of their unknown function.) In this paper, Budnik and colleagues show that a retrotransposon called Copia is also packaged in EVs and released by cells. This finding opens the possibility that, similar to Arc, these mysterious genomic residents might also have a role in intercellular communication.
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